Field of the Invention
The present invention relates to the fields of molecular biology and reproductive technology. In particular, the invention relates to a cation channel protein expressed specifically in sperm cells, nucleic acids encoding the protein, cells engineered to express the protein, assays for compounds affecting the activity of the protein, and the use of such compounds in the treatment or causation of infertility, or as a means of contraception or animal control.
Description of the Related Art
Sperm and ova reciprocally interact in mammalian fertilization (Wassarman et al. (2001), Nature Cell Biology 3:E59-E64; Yanagimachi (1994), in The Physiology of Reproduction, Knobil & Neill eds. (Raven Press, New York), pp. 189-315). To reach the site of fertilization, sperm must travel relatively long distances and become primed for fertilization of the ova through capacitation and other processes. Once they arrive at the surface of an ovum, sperm interact with ovum extracellular matrix glycoproteins including the zona pellucida proteins. Sperm release acidic material during the acrosome reaction, a signaling event that presumably involves the opening of Ca2+ channels and the influx of Ca2+ into the sperm heads (O'Toole et al. (2000), Mol. Biol. Cell 11:1571-84). The TRPC2 protein, a putative Ca2+-permeant channel, has recently been implicated in the acrosome reaction (Jungnickel et al. (2001), Nat. Cell Biol. 3:499-502). Penetration of sperm through the thick outer layer of the ovum is achieved through chemical lysis of the ovum coat and/or the mechanical motion of sperm (Bedford (1998), Biol. Reprod. 59:1275-87). Following infiltration of the ovum zona pellucida coat, the sperm membrane fuses with that of ovum. Fusion is followed by activation of the fertilization process, beginning with Ca2+ oscillations in the ovum (Wassarman et al. (2001), supra; Yanagimachi (1994), in The Physiology of Reproduction, Knobil & Neill eds. (Raven Press, New York), pp. 189-315).
Ca2+ and cyclic nucleotides control sperm motility (Tash (1990), in Controls of Sperm Motility: Biological and Clinical Aspects, Gagnon ed. (CRC Press, Boca Raton), pp. 229-240; Darszon et al. (1999), Physiol. Rev. 79:481-510; Hyne and Garbers (1979), Proc. Natl. Acad. Sci. USA 76:5699-703) and several voltage-dependent Ca2+ channel (CaV) mRNAs and cyclic nucleotide-gated (CNG) channel proteins have been detected in sperm cell precursors (Darszon et al. (1999), Physiol. Rev. 79:481-510; Serrano et al. (1999), FEBS Lett. 462:171-6; Weyand et al. (1994) Nature 368:859-63; Wiesner et al. (1998), J. Cell Biol. 142:473-84). Furthermore, low voltage activated, dihydropyridine-sensitive “T-type” channels (Santi et al. (1996), Am. J. Physiol. 271):C1583-93; Arnoult et al. (1996), Proc. Natl. Acad. Sci. USA 93:13004-9) and pharmacologically defined N- and R-type currents have been measured in spermatogenic cells (Wennemuth et al. (2000). J. Biol. Chem. 275:21210-7). The role of these channels, however, in spermatogenesis or mature sperm function is not known.
Recently, a voltage-gated channel (CatSper1) was discovered that is required for normal fertility of mice (Ren et al. (2001), Nature 413:603-9).